DESCRIPTION (Applicant's abstract): The pulmonary circulation is generally regarded as a largely passive circuit in which blood flow distribution is largely determined by the hydrostatic gradient due to gravity - a perspective that has dominated both the interpretation and direction of studies related to pulmonary perfusion for the last three decades. However, recent studies using high resolution and experiments performed in microgravity have shown that pulmonary perfusion is much more heterogeneous than can be explained by gravity alone. In this proposal we will build on our understanding of perfusion heterogeneity to elucidate the mechanisms, other than gravity, that determine blood flow distribution in the lung. High resolution measurements of blood flow distribution are needed to investigate mechanisms of perfusion heterogeneity over a range of scales from the main pulmonary arteries to the alveolar capillaries. To this end, we have established methods needed to explore the spatial distribution of pulmonary blood flow throughout the entire lung at the microscopic level. Our Specific Aims are: 1) To obtain measurements of regional pulmonary perfusion at the alveolar capillary level in rats rabbits, dogs, and ferrets and determine if there is a unit in which flow is uniform. 2) To quantify the regional variability in capillary volume, alveolar volume, and vasomotion and determine their contribution to perfusion heterogeneity. 3) To determine if hypoxic pulmonary vasoconstriction causes uniform or heterogeneous redistribution of flow during acute and chronic global hypoxia. 4) To determine whether the new concepts of pulmonary perfusion heterogeneity apply to humans by studying the distribution of pulmonary blood flow in baboons. Statistical methods for analyzing spatial distributions of microspheres will be used to characterize regional perfusion distribution. An integral outgrowth of these studies will be a new model for pulmonary blood flow, reconciling previous observations and new insights from this project. In addition to this new information on basic lung function, pulmonary perfusion distributions can now be explored in small-animal disease models.